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- EMDB-0598: Structure of a drug-like molecule stalled ribosome nascent chain ... -

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Entry
Database: EMDB / ID: EMD-0598
TitleStructure of a drug-like molecule stalled ribosome nascent chain complex (PCSK9_RNC) in non-rotated state with PP tRNA
Map dataPF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA. Map is sharpened.
Sample
  • Complex: Drug-like molecule stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA
    • RNA: human ribosome with nascent chain
Function / homology
Function and homology information


adenylosuccinate lyase / N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity / (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate lyase (fumarate-forming) activity / eukaryotic 80S initiation complex / : / negative regulation of protein neddylation / translation at presynapse / negative regulation of endoplasmic reticulum unfolded protein response / 'de novo' AMP biosynthetic process / oxidized pyrimidine DNA binding ...adenylosuccinate lyase / N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity / (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate lyase (fumarate-forming) activity / eukaryotic 80S initiation complex / : / negative regulation of protein neddylation / translation at presynapse / negative regulation of endoplasmic reticulum unfolded protein response / 'de novo' AMP biosynthetic process / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / axial mesoderm development / embryonic brain development / ribosomal protein import into nucleus / protein tyrosine kinase inhibitor activity / positive regulation of respiratory burst involved in inflammatory response / negative regulation of formation of translation preinitiation complex / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of gastrulation / nucleolus organization / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 90S preribosome assembly / IRE1-RACK1-PP2A complex / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / TNFR1-mediated ceramide production / TORC2 complex binding / negative regulation of RNA splicing / negative regulation of DNA repair / GAIT complex / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / supercoiled DNA binding / oxidized purine DNA binding / neural crest cell differentiation / NF-kappaB complex / middle ear morphogenesis / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / positive regulation of ubiquitin-protein transferase activity / negative regulation of phagocytosis / A band / rRNA modification in the nucleus and cytosol / erythrocyte homeostasis / Formation of the ternary complex, and subsequently, the 43S complex / alpha-beta T cell differentiation / cytoplasmic side of rough endoplasmic reticulum membrane / regulation of G1 to G0 transition / exit from mitosis / laminin receptor activity / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of translation involved in cellular response to UV / protein-DNA complex disassembly / pigmentation / protein kinase A binding / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / negative regulation of ubiquitin protein ligase activity / 'de novo' IMP biosynthetic process / optic nerve development / Ribosomal scanning and start codon recognition / ion channel inhibitor activity / response to aldosterone / Translation initiation complex formation / retinal ganglion cell axon guidance / mammalian oogenesis stage / fibroblast growth factor binding / homeostatic process / positive regulation of mitochondrial depolarization / G1 to G0 transition / activation-induced cell death of T cells / macrophage chemotaxis / positive regulation of T cell receptor signaling pathway / lung morphogenesis / negative regulation of peptidyl-serine phosphorylation / iron-sulfur cluster binding / negative regulation of Wnt signaling pathway / positive regulation of activated T cell proliferation / monocyte chemotaxis / Protein hydroxylation / regulation of cell division / BH3 domain binding / cysteine-type endopeptidase activator activity involved in apoptotic process / mTORC1-mediated signalling / SARS-CoV-1 modulates host translation machinery / Peptide chain elongation / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Selenocysteine synthesis / positive regulation of signal transduction by p53 class mediator / Formation of a pool of free 40S subunits / blastocyst development / ubiquitin ligase inhibitor activity / Eukaryotic Translation Termination / phagocytic cup / negative regulation of respiratory burst involved in inflammatory response / Response of EIF2AK4 (GCN2) to amino acid deficiency / SRP-dependent cotranslational protein targeting to membrane / Viral mRNA Translation / protein localization to nucleus / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)
Similarity search - Function
Adenylosuccinate lyase PurB, C-terminal / : / Adenylosuccinate lyase C-terminal / Adenylosuccinate lyase / Fumarate lyase, conserved site / Fumarate lyases signature. / Fumarate lyase family / Fumarate lyase, N-terminal / Lyase / Fumarase/histidase, N-terminal ...Adenylosuccinate lyase PurB, C-terminal / : / Adenylosuccinate lyase C-terminal / Adenylosuccinate lyase / Fumarate lyase, conserved site / Fumarate lyases signature. / Fumarate lyase family / Fumarate lyase, N-terminal / Lyase / Fumarase/histidase, N-terminal / L-Aspartase-like / 40S ribosomal protein SA / 40S ribosomal protein SA, C-terminal domain / 40S ribosomal protein SA C-terminus / Ribosomal protein L6, N-terminal / Ribosomal protein L6, N-terminal domain / Ubiquitin-like protein FUBI / Ribosomal protein L30e / Ribosomal protein L2, archaeal-type / Ribosomal L15/L27a, N-terminal / Ribosomal protein L28e / Ribosomal protein L23 / Ribosomal protein L18/L18-A/B/e, conserved site / Ribosomal protein L18e signature. / Ribosomal L28e/Mak16 / Ribosomal L28e protein family / Ribosomal protein L18e / Ribosomal protein 60S L18 and 50S L18e / : / Ribosomal protein S26e signature. / Ribosomal protein L41 / Ribosomal protein L41 / metallochaperone-like domain / TRASH domain / Ribosomal protein S26e / Ribosomal protein S21e, conserved site / Ribosomal protein S26e superfamily / Ribosomal protein S26e / Ribosomal protein S21e signature. / : / Ribosomal protein S12e signature. / Ribosomal protein S12e / Ribosomal protein S5, eukaryotic/archaeal / Ribosomal protein S19e, conserved site / Ribosomal protein S19e signature. / Ribosomal protein L29e / Ribosomal L29e protein family / Ribosomal protein L13e, conserved site / Ribosomal protein L13e signature. / Ribosomal protein S21e / Ribosomal protein S21e superfamily / Ribosomal protein S21e / Ribosomal protein S2, eukaryotic / Small (40S) ribosomal subunit Asc1/RACK1 / S27a-like superfamily / Ribosomal protein L22e / Ribosomal protein L22e superfamily / Ribosomal L22e protein family / Ribosomal protein L38e / Ribosomal protein L38e superfamily / Ribosomal L38e protein family / 40S Ribosomal protein S10 / Ribosomal protein S10, eukaryotic/archaeal / Ribosomal protein L27e, conserved site / Ribosomal protein L27e signature. / Ribosomal protein L44e signature. / Plectin/S10, N-terminal / Plectin/S10 domain / Ribosomal protein L10e, conserved site / Ribosomal protein L10e signature. / Ribosomal protein S25 / S25 ribosomal protein / Ribosomal protein L10e / Ribosomal protein L13e / Ribosomal protein S27a / Ribosomal protein L13e / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein L19, eukaryotic / Ribosomal protein S2, eukaryotic/archaeal / Ribosomal protein S8e subdomain, eukaryotes / Ribosomal protein S17e, conserved site / Ribosomal protein S17e signature. / 60S ribosomal protein L18a/ L20, eukaryotes / Ribosomal protein S30 / : / Ribosomal protein S30 / 40S ribosomal protein S29/30S ribosomal protein S14 type Z / Ribosomal protein S7e signature. / : / Ribosomal protein L24e, conserved site / Ribosomal protein L19/L19e conserved site / Ribosomal protein L19e signature. / Ribosomal protein L24e signature. / Ribosomal protein S3, eukaryotic/archaeal / Ribosomal protein L44e / Ribosomal protein L44 / Ribosomal protein L34e, conserved site / Ribosomal protein L34e signature. / Ribosomal protein L5 eukaryotic, C-terminal
Similarity search - Domain/homology
FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / Small ribosomal subunit protein uS5 / Large ribosomal subunit protein eL33 / Large ribosomal subunit protein uL30 / Large ribosomal subunit protein uL22 / Small ribosomal subunit protein eS4, Y isoform 1 / Small ribosomal subunit protein uS3 / Small ribosomal subunit protein eS12 ...FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / Small ribosomal subunit protein uS5 / Large ribosomal subunit protein eL33 / Large ribosomal subunit protein uL30 / Large ribosomal subunit protein uL22 / Small ribosomal subunit protein eS4, Y isoform 1 / Small ribosomal subunit protein uS3 / Small ribosomal subunit protein eS12 / Large ribosomal subunit protein eL13 / Large ribosomal subunit protein uL16 / Large ribosomal subunit protein uL6 / Large ribosomal subunit protein eL22 / Large ribosomal subunit protein uL4 / Small ribosomal subunit protein eS19 / Large ribosomal subunit protein uL3 / Large ribosomal subunit protein uL13 / Small ribosomal subunit protein eS27 / Large ribosomal subunit protein uL29 / Large ribosomal subunit protein uL15 / Large ribosomal subunit protein uL18 / Large ribosomal subunit protein eL21 / Large ribosomal subunit protein eL28 / Small ribosomal subunit protein uS4 / Small ribosomal subunit protein uS7 / Small ribosomal subunit protein eS10 / Large ribosomal subunit protein eL29 / Large ribosomal subunit protein eL34 / Large ribosomal subunit protein eL14 / Small ribosomal subunit protein uS10 / Small ribosomal subunit protein eS1 / Large ribosomal subunit protein uL24 / Large ribosomal subunit protein eL15 / Large ribosomal subunit protein eL27 / Large ribosomal subunit protein eL43 / Large ribosomal subunit protein eL37 / Small ribosomal subunit protein eS7 / Small ribosomal subunit protein eS8 / Small ribosomal subunit protein uS8 / Small ribosomal subunit protein uS9 / Small ribosomal subunit protein uS11 / Small ribosomal subunit protein uS12 / Small ribosomal subunit protein uS13 / Small ribosomal subunit protein uS14 / Small ribosomal subunit protein uS15 / Small ribosomal subunit protein uS17 / Large ribosomal subunit protein eL8 / Large ribosomal subunit protein uL23 / Small ribosomal subunit protein eS6 / Large ribosomal subunit protein uL14 / Small ribosomal subunit protein uS19 / Small ribosomal subunit protein eS24 / Small ribosomal subunit protein eS25 / Small ribosomal subunit protein eS26 / Small ribosomal subunit protein eS28 / Ubiquitin-like FUBI-ribosomal protein eS30 fusion protein / Large ribosomal subunit protein eL30 / Large ribosomal subunit protein eL39 / Large ribosomal subunit protein eL31 / Large ribosomal subunit protein eL32 / Large ribosomal subunit protein uL5 / Large ribosomal subunit protein uL2 / Small ribosomal subunit protein eS32 / Ubiquitin-ribosomal protein eS31 fusion protein / Ubiquitin-ribosomal protein eL40 fusion protein / Large ribosomal subunit protein eL38 / Small ribosomal subunit protein eS21 / Small ribosomal subunit protein RACK1 / Large ribosomal subunit protein eL24 / Large ribosomal subunit protein eL42 / Large ribosomal subunit protein eL19 / Large ribosomal subunit protein eL20 / Large ribosomal subunit protein eL6 / Large ribosomal subunit protein eL18 / Adenylosuccinate lyase / Large ribosomal subunit protein uL14 / Large ribosomal subunit protein eL36
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsLi W / Cate JHD
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research InstituteR01-GM065050 United States
CitationJournal: Nat Struct Mol Biol / Year: 2019
Title: Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule.
Authors: Wenfei Li / Fred R Ward / Kim F McClure / Stacey Tsai-Lan Chang / Elizabeth Montabana / Spiros Liras / Robert G Dullea / Jamie H D Cate /
Abstract: The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ...The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyl-transfer RNA 3'-CCA end is improperly docked in the peptidyl transferase center. Selections of messenger RNAs from mRNA libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination or even enhance translation, depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins of therapeutic interest.
History
DepositionFeb 21, 2019-
Header (metadata) releaseMar 20, 2019-
Map releaseMar 20, 2019-
UpdateJun 19, 2019-
Current statusJun 19, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.024
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.024
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  • Surface view with fitted model
  • Atomic models: PDB-6olz
  • Surface level: 0.024
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0598.png

Downloads & links

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Map

FileDownload / File: emd_0598.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA. Map is sharpened.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.22 Å/pix.
x 400 pix.
= 488. Å		1.22 Å/pix.
x 400 pix.
= 488. Å		1.22 Å/pix.
x 400 pix.
= 488. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.22 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.022 / Movie #1: 0.024
Minimum - Maximum-0.057956874 - 0.10376459
Average (Standard dev.)0.000268779 (±0.007156887)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 488.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.221.221.22
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z488.000488.000488.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0580.1040.000

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Supplemental data

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Additional map: PF846 stalled human ribosome nascent chain complex (PCSK9-RNC)...

Fileemd_0598_additional.map
AnnotationPF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA. Map is not sharpened.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map of PF846 stalled human ribosome nascent...

Fileemd_0598_half_map_1.map
AnnotationHalf map of PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map of PF846 stalled human ribosome nascent...

Fileemd_0598_half_map_2.map
AnnotationHalf map of PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Drug-like molecule stalled human ribosome nascent chain complex (...

EntireName: Drug-like molecule stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA
Components
  • Complex: Drug-like molecule stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA
    • RNA: human ribosome with nascent chain

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Supramolecule #1: Drug-like molecule stalled human ribosome nascent chain complex (...

SupramoleculeName: Drug-like molecule stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HeLa
Molecular weightTheoretical: 4.3 MDa

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Macromolecule #1: human ribosome with nascent chain

MacromoleculeName: human ribosome with nascent chain / type: rna / ID: 1
Details: Nascent chain sequence including CDH1 domain V and PCSK9 1-35
Source (natural)Organism: Homo sapiens (human)
SequenceString:
SDVNDNAPIP EPRTIFFCER NPKPQVINII DADLPPNTSP FTAELTHGAS ANWTIQYNDP TQESIILKPK MALEVGDYKI NLKLMDNQNK DQVTTLEVSV CDCEGAAGVC RKAQPVEAGL QIPAILGILG MGTVSSRRS WWPLPLLLLL LLLLGPAGAR AQEDED

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.8
GridDetails: unspecified
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 4 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 7214
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Overall B value: 80
Output model

PDB-6olz:
Human ribosome nascent chain complex (PCSK9-RNC) stalled by a drug-like molecule with PP tRNA

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